1-alkoxy ethinyl-2-alkenyl dodecahydrophenanthrene compounds



I-A KQX D DECA- THR NE CQM QU DS Lewis H. Sarett, Princeton, N. ,L,assignor to Merck & Co., Inc., Rahway, N. 1., a corporation of NewJersey N a nspp at on O to e 12,

Serial No, 540,166

12 Claims. (Cl. 260-3403) This invention relates tonovelpolyhydrophenanthrene compounds and processes of obtaining the'same. More particularly, it is concerned with new tertiary alcohol's ofthe polyhydrophenanthrene series which have an unsaturated aliphaticradical attached to the same ring carbon atom as the tertiary hydroxylgroup, and methods of preparing these compounds. Specifically, itrelates to new dodecahydrophenanthrene compounds containing-at 0-1 ahydroxyl group and an unsaturated aliphatic radical, and processes forthe preparation of these compounds.

This application is a continuation-in-part ofmy copending applicationSerial No. 308,172, filed September 5, 1952, now abandoned, and SerialNo; 310,133,=filed September 17, 1952, now abandoned. v

Tertiary dodecahydrophenanthrene carbinols of :the

formula:

CH: .3 R. 0 31 4a 1 R2 5 6 4b10a OK A B 1 8a 10 s 9 wherein R representsa keto or hydroxyl group, R represents an unsaturated aliphatic radical,and R represents a substituted or unsubstituted aliphatic hydrocarbonradical are valuable as intermediates in the preparation of steroidcompounds. Thus, these tertiary carbinols having suitable unsaturatedaliphatic radicals at -;positions 1 and 2 can be further treated toeffect ring closure, thereby forming ring D of the steroid system andproviding a functional substituent at the 17 position of the steroid.

It is an object of the present invention to p1 ,vide noveldodecahydrophenantbrene compounds having at position la tertiaryhydroxyl and a substituted or unsubstituted unsaturated aliphaticradical, and processes of obtaining the same. Another object of myinvention is to provide novel dodecahydrophenanthrene compounds having.a tertiary hydroxyl and a substituted or unsubstitutedunsaturatedaliphatic radical in position 1, and inaddition functional substituentsin positions 2, 4, and 7. It is a further object of this invention toprovide novel processes for the preparation of these new compounds.

Other objects will be apparent from the detaileddescription of myinvention hereinafter provided.

In accordance with my invention, Ihayefound that dodecahydrophenanthrenecompounds having in ring C the structure:

wherein R represents a keto or hydroxyl ,group and R; v

.phatic hydrocarbon radical. are valuable as intermediates in thesynthesis of therapeutically important steroid compounds such ascortisone 2,853,496 Patented Sept. 23, 1958 represents an unsaturatedorganic hydrocarbon radical are converted by reaction with anlunsaturated metallo-organic compound to the corresponding tertiary carbinolshaving in ring C the structure:

wherein R and. 1 a hes n se n d a ove and R2 represents the unsaturatedradical of the mctallo-organic compound. The1-keto-2,4b-dimethyl-dodecahydrophenanthrene compounds employed in thisreaction can be saturated or unsaturated, and may, in addition, containsubstituents in rings A and ;B of the dodecahydrophenanthrene nucleus.Thus, rings A and B can contain substituents such as hydroxy,acy1oxy,alkyl, ether, ketal, and the like, which do not affect theprocess of my invention. When starting materials containing anotherreactive keto substituent in rings A or B are employed, this group alsoreacts forming a'ditertiary carbinol. "However, such reactive ketogroups in rings A and B can be blocked or protected by converting theketo group to an enol ether or a ketal derivative which on hydrolysis isreconverted to a keto substituent.

The novel process of rny' invention is of particular value in thepreparation of the'n'ovel 7-ketal and 7-enol ether derivatives ofdodecahydrophenanthrene compounds of the formula:

wherein Rrepresents-a keto or-hydroxyl group, R represents anunsaturated aliphatic hydrocarbon radical, R2 represents asu'bstitutedor unsubstituted unsaturated ali- These compounds, which and'the like,are obtained by reacting the corresponding-1:keto:dodecahydrophenanthrene with an unsaturatedmetalloeorganiccompound. i

The 7-,enol ether and 7-ketal derivatives of the dodecahydrophenanthrenecompounds of the structural 'formula:

w e e n R prese t a t Qrh dmx qupandki es t a aasaw a s al ha i h os bdnrasiic'a are useful as starting materials in the processes of the P eseni en Th 9 s h rs' o the t'n smrla tom-mg 4! wherein R is a hydrocarbonradical, are suitable starting materials. The methyl and ethyl enolethers, which are readily prepared, are particularly suitable asstarting materials. Cyclic ketal derivatives such as the 7-ethylenedioxyderivative of the formula and the corresponding ditfhioketal of theformula:

are also useful in the processes of the present invention. Similarly,other cyclic ketal derivatives such as the trimethylene, propylene andbutylene ketals to protect the 7-keto substituent. Upon hydrolyzingthese enol ether and ketal derivatives with acid, the protectingsubstituent is cleaved and the 7-keto compound having a double bond inposition 8,8a is obtained.

Thus, in accordance with one embodiment of my invention, the startingcompounds can be reacted with a Grignard. type metallo-organic compoundderived from substituted or unsubstituted alkenes or alkynes. Forexample, 2,4b-dimethyl-2-methallyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1 ol- 4-one, or thecorresponding 1,4-dione compound, can be reactedwithmagnesium-organocompounds such as an alkene (inter alia, allyl and the like), or analkyne (inter alia, acetylene, ethoxy acetylene, and the like),magnesium halide to obtain the corresponding 1-hydroxyl-alkenyl orl-hydroxy-l-alkynyl derivative.

This addition reaction as illustrated by the preparation I of 1ethoxyethinyl 2,4b dimethyl 2 methallyl 7- The tertiary alcohol isconveniently recovered smiths hydrolysis mixture'by extraction with asuitable organic solvent and evaporation ofthe resulting extract.

This process is carried outin similar manner when other organicmagnesium-halides areemployed. Any suitable solvent can be used in placeof the benzene.

ethereal solution, the addition reaction can readily be carried out inan ethyl ether medium. However, solvents Since the I Grignard typecompounds are conveniently prepared in such as toluene, xylene,isopropyl ether, or hydrocarbon ether mixtures are equally satisfactory.

The amount of the metallo-organic compound used does not appear to becritical in the process. For optimum results I generally prefer to useabout 2-5 times the theoretical quantity of organo-magnesium halide,although the operativeness of the process is not efifected by anincrease or a decrease in the quantity of reagent. When adodecahydrophenanthrene-4-ol-l-one is employed as starting material,adjustments must be made in the amount of reagent charged since one moleof the Grignard type compound will be consumed in reaction with the freehydroxy substituent. On hydrolysis the complex so formed is decomposedand the hydroxyl group is regenerated.

The complexes formed as intermediates in these Grignard type reactionsare decomposed to the l-hydroxy- 1-alkenyl or the l-hydroxy-l-alkynylderivatives by the addition of the reaction mixture to water. Thedesired tertiary alcohol is readily recovered from the aqueous mixtureby extraction with a suitable water-immiscible solvent as' discussedabove.

Thus, in accordance with one embodiment of my in-' vention,2,4b-dimethyl 2 methallyl 7 ethylendioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4- ol-l-one is reacted with ethoxyacetylenemagnesium bromide or with allyl magnesium bromide to obtainl-ethoxyethinyl 2,4b dimethyl-2-methallyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1,4 -diol, and1-a.llyl-2,4b-dimethyl-2-methallyl-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1',4-diol, respectively.Similarly, thefcorresponding 1,4-dione on reaction with these magnesiumbromide compounds yield the corresponding 1-ol-4-one compounds.Alternatively, the 1,4-diol compounds can be oxidized by treatment withsuitable oxidizing agents, for example, the chromium trioxide-pyridinecomplex to oxidize the 4-hydroxy substituent and obtain the l-ol-4- onecompound.

Alternatively, in accordance with a further embodiment of my invention,the novel dodecahydrophenanthrene compounds of the present invention arealso conveniently obtained by-reacting thel-keto-dodecahydrophenanthrene compounds with an alkali metal oralkaline earth metal acetylide. Since acetylides such as. lithium andpotassium acetylides are'ordinarily prepared by the reaction of the freemetal with acetylene in liquid ammonia, it is found most convenient tocarry out the addition reaction in the liquid ammonia solution of themetal acetylides. The reaction is allowed to proceed as the ammonia isremoved and the reaction mixture is gradually brought to roomtemperature. After the liquid ammonia is completely replaced by an inertorganic solvent, the reaction product is decomposed and the isolationcarried out in accordance with'conventional procedures. Thisethinylation reaction can also be carried out in a tertiary alcohol suchas tertiary butanol or isopropanol.

added'to an alcoholic solution of the alkali metal in the presence ofan-excess up to about 5 to 10 times the required'theoretical amount ofalkali acetylide, since maximum yields of the desired product areobtained using a large excess of the alkali acetylide under optimumconditions.

Thus, pursuant to this embodiment of my invention,'2,4b-dimethyl-Z-methallyl 7 ethylenedioxy-l,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrene-l ,4-dione, or the corresponding4-ol-1-one compound is reacted with lithium or potassium acetylide toobtain the corresponding l-ethinyl-l-hydroxy compound. In the samemanner, other similar dodecahydrophenanthrene compounds containing adifierent unsaturated hydrocarbon radical in place of the Z-methallylsubstituent, and/or a different blocking or protecting group such as anenol ether or another ketal derivative in place of the ethylenedioxy\Vhen 'thesealcohols are employed as solvents, the ketone is asssaassubstituent can be reacted with a metal ac,etylide to ob.- tain thecorresponding l--ethinyl-l-hydroxy derivatives.

In accordance with a further "embodiment of myhinvention, I have foundthat these tertiary alcohols, of the dodecahydrophenanthrene series canalso be prepared by reacting the 1-keto-dodecahydrophenanthrene compoundwith a brominatedlower aliphatic acid ester in the presence of metalliczine. This reaction is conveniently carried out in an inert solventmedium such as an ether or an aromatic hydrocarbon, preferably 'atreflux temperature.

In the foregoing description of my invention, the reactions with2-methallyl-7-ethylenedioxy compounds were presented as illustrativeembodiments 'of this invention. It will be readily apparent to thoseskilled in the art that the process ofmy invention can be applied toother dodecahydrophenanthrenecompounds having different unsaturatedaliphatic radicals in the 2 position and different blocking orprotecting groups in the 7 position. Thus, in place of using theZ-methallyl compounds, I can employ other dodecahydrophenanthrenecompounds having different unsaturated aliphatic radicals such as the2-allyl, 2-propargyl, and the like, to obtain the corresponding tertiaryalcohols. Similarly, in place of employing compounds having the 7-ketosubstituent protected by the lethylenedioxy compounds, I can use othersimilar compounds having difierent protective substituents 'in the 7position.

- Thus, for example, the 7-keto substituent can beblocked by theformation of an enol ether or another ketal derivative which can bereadily hydrolyzed to regenerate the 7-keto substituent.

The tertiary alcohols of the dodecahydrophenanthrene series prepared inaccordance with the processes of the present invention are valuableasintermediates in the preparation of steroids by total synthesis. Thenovel carbinolsof this invention having an unsaturated aliphatic radicalof less than 5 carbon atoms in the 1 position are of particular value asintermediates in the synthesis of steroids. These novel compounds aftersuitable modification of the side chain can be treated toeifect ringclosure and the formationof steroidal substances.

For example, the 2,4b-dimethyl-2methallyll-ethoxyethinyl-7-ethylenedioxyl 1,2,3,4,4a,4b,-5,6,7,8,10,10a--dodecahydrophenanthrene-l-ol-4-one of M. P, -13.1132 C. can beconverted to the valuable adrenal hormones 1 l-dehydrocorticosterone andcortisone .as follows:

When this ethoxyethinyl compound is treated with dilute sulfuric acid,2,4b dimethyl-2=methallylrlfcarboethoxymethylene-7-ethylenediOxy-:1,2,3,4,4a,4b,5;6,7,8,l0,

10a-dodecahydrophenanthrene-4eone, .M. .P. 9496 C. is

obtained. Upon hydrolyzing this compound .with alkali the correspondingfree acid, M. P. .203..205 :C. -iS P I'O' duced. Reduction of thisketoacid with sodium borohydride to the 4-hydroxy acid, followedbyreduction of the conjugated double bond with,potassium-arnmonia-isopropyl alcohol affords2,4bedimethyl-ll-carboxymethyl-2- methallyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10.10adodecahydrophenanthrene-4-ol,M. P. 255...257 C. Reduction of this carboxymethyl compound withlithiumaluminum hydride yields the corresponding 1=(fl-hydroxyethyl)derivatives M. P. 199-201 C..and,210.2l l- C., which on reaction withp-toluene sulfonyl chloride in the presence of pyridinegivesthel-(fl-toluene sulfon-ate), M. P. 157-158 C. Successive oxidations ofthis monotoy'slate derivative with the chromium trioxide-pyridinecomplex, with oxmium .tetroxide and with periodicacid yields2,4b-dimethyl- 1 3, (fl-p-toluenesulfonyloxyethyl) .-2- acetonyl 7ethylenedioxy l,2,3,4,4a,4b,5 6,7,8,10.10adodecahydrophenanthrene-4-one,M. 'P. 105-108" C. Upon reacting this product with sodium m'ethoxidedl-3- ethylenedioxy A 17a pregnene 111,20 dione, M. P, 212214 C. isobtained Which on @qtfilibration with alkali gives the 3-ethylenedioxyderivative of.dl-11-.keto progesterone, M. P. 181-1825 C. "Acidhydrolysis of this;product affords dl-111-keto-progesterone. Reaction ofI the 3-ethylenedioxy derivative of dl-ll-ketoprogesterone with anoxalyl ester yields the corresponding 2'l-oxalyl ester compound which onhydrolysis is. converted to the free'acid. Resolution of thedl-21-oxalyl acid by means of the strychnine salt followed by hydrolysisof the oxalyl acid group gives 3-ethylenedioxy-A -pregnene-11,20-dione,M. P. -1765 C. which on hydrolysis with acid aifordsll-ketoprogesterone, identical with material prepared from naturalsources. Iodination and acetoxylation of the Zl-oxalyl acid of3-ethylenedioxy-A -pregnene-11,20- dione obtained as described aboveyields successively crystalline 3 ethylenedioxy-Z1-iodo-A-pregnene-11,20-dione and 3-ethylenedioxy-A -pregnene-2l-ol-11,20-dioneacetate, M. P. 193.5-194" C. Acid hydrolysis of this latter compoundyields ll-dehydrocorticosterone identical with the product obtained fromnatural sources. Conversion of the3-ethylenedioxy-M-pregnene-2l-ol-11,20-dione acetate to the 20cyanhydrin, M. P. dec. 220-224 C., and dehydration of this product givesthe A -20-cyanopregnadiene, M. P. 203 C. which on oxidation withpotassium permanganate yields 3 ethylenedioXy-A -pregnene-17,21-diol-1l,20-dione acetate, dec. 262267 C. Acid hydrolysis of the lattercompound yielded cortisone acetate.

Alternatively, following procedures described in detail in co-pendingapplication Serial No. 310,133, 2,4b-dimethyl 1carboxymethyl-2-methallyl-7-ethylene-dioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4- 01, which can be prepared as described above,can be converted to dl-ll-ketoprogesterone as follows: 2,4b-dimethyl 1carboxymethyl-Z-methallyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene 4- 01 is reactedwith an oxidizing agent to produce the corresponding 4-keto compoundwhich is then reacted with an esterifying agent to form thecorresponding 2,4bdimethyl 1carboalkoxymethyl-2-methallyl7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one. Reaction ofthis compound with ozone followed by hydrolysis of the ozonide resultsin the obtainment of 2, 4b dimethyl-l-carboalkoxymethyl-Z-acetonyl 7ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,l0,l0a-dodecahydropenanthrene-4-one.The latter compound is reacted, under substantially anhydrousconditions, with a' strong alkali thereby forming A-3-ethylenedioxy-11,16, 20 triketopregnene. The A-3-ethylenedioxy-11,16,20- triketopregnene is reacted with an organicsulfonyl halide thereby forming the corresponding sulfonate ester of A 3ethylenedioxy-l1,20-diketo-16-hydroxy-pregnadiene, which is reacted withhydrogen in the presence of a hydrogenation catalyst to produce A-3-ethylenedioxy- 11,20 diketo-pregnene. The A -3-ethylenedioxy-11,20:diketo-pregnene is then reacted with an aqueous mineral acid solutionwhereupon the ethylenedioxy substituent attached to the .3-carbon atomis hydrolyzed and, at the same time, the double bond shifts from ring Bto ring A to form A -3,1 1,20-triketorpregnene.

The new compounds of the present invention having a 4-hydroxysubstituent can be readily oxidized by treat ment with an-oxidizingagent such as pyridine-chromium trioxide complex to convert thissubstituent to a keto group.

In somewhat similar manner, 2,4b-l-allyl-2-methallyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahy: drophenanthrene-l-ol-4-oneobtained in accordance with thepresent invention can be converted tovaluable steroid compounds. Oxidation of this 1-allyl-2-methallylcompound, first with osmium tetraoxide to form thecOIresponding'2-acetonyl compound, and then with periodic acid affords 2 ,4bdimethyl-7-ethylene dioxy2 acetonyl 1- formylmethyl1,2,3,4,4a,5,6,7,8,10,10a dodecahydrophenantbrene=4-one. Treatment ofthis compound with anaqueous solution of potassium hydroxide prod u c es4 -3-.ethylenedioxypregnadiene-11,20rdione which uponselective;hydrogenat ionin thepresence ofpalladiumaffords"thezcorresponding.Mrpregnene compound. The. A

3-ethylenedioxypregnene-11,20 dione can then be converted to cortisoneas described above. The 2,4b-dimethyl 7 ethylenedioxy l carboloweralkoxymethylZ-methallyl-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1-ol-4-onecompounds prepared as described herein can be converted to thecorresponding l-carb-lower alkoxy methylene derivative by treatment withthionyl chloride. This l-carb-lower alkoxy methylene compound can thenbe converted to cortisone by the processes shown above.

The 2,4b-dimethyl-2-methallyl-7-ethylenedioxy-123,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-ol-1- one, or thecorresponding 1,4-dione compound, employed as starting materials in theexamples illustrating this invention, can be prepared as disclosed andclaimed in copending application Serial No. 445,921, filed July 26, 1954, now U. S. Patent 2,810,729.

Thus, these compounds can be prepared as follows:

After standing a few minutes at room temperature, a

finely divided precipitate of potassium iodide separated from thereaction mixture. After 24 hours at room temperature, water was addedand the organic material extracted with ether. The ethereal solution wasevaporated to dryness and the residue chromatographed on alumina.

Consecutive fractions of the eluate (petroleum etherether) yield twoisomeric forms of 2,4b-dimethyl-2- propargyl 7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol-l-onemelting at 180 C. and 126-128" C. respectively. pounds with acid yieldsthe two isomeric 2,4b-dimethyl- 2 propargyl1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4-ol-l,7-diones.

In similar manner2,4b-dimethyl-2-propargyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenan- 10,10adodecahydrophenanthrene-1,4,7-trione and the corresponding4-ol-1,7-dione compound can be prepared as follows:

fi-Ethoxy-propionaldehyde is reacted with ethyl magnesium bromide toproduce 1-ethoxy-3-hydroxy-pentane which is oxidized with chromic acidto form l-ethoxy- 3-keto-pentane. Upon reacting this compound with ethylortho-formate in alcohol solution containing a trace of hydrogenchloride, 1,3,3-triethoxy-pentane is obtained.

Hydrolysis of these com- Reaction of the latter compound with hotpotassium acid sulfate produces 3-ethoxy-1,3-pentadiene. When the 3-ethoxy-l,3-pentadiene is condensed with benzoquinone in accordance withthe Diels-Alder procedure, S-methyl- 6 ethoxy l,4,4a,5,8,8ahexahydronaphthalene 1,4- dione is obtained. Hydrogenation of thiscompound in the presence of Raney nickel produced 5-methyl-6- ethoxy1,2,3,4,4a,5,8,8a octahydronaphthalene 1,4- dione. Further reduction ofthis compound by reaction with lithium aluminum hydride affords thecorresponding diol 5 methyl 6 ethoxy 1,2,3,4,4a,5,8,8aoctahydronaphthalene-1,4-diol. Upon reacting this compound with diluteacetic acid, 5-methyl-6-keto-perhydronaphthalene-1,4-diol is obtained.When the S-methyl- 6-keto-perhydronaphthalene is condensed with methylvinyl ketone in an alkaline reaction medium 7-keto-4bmethyl1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-1,4-diol isobtained. Upon reacting the latter product with ethylene glycol in thepresence of p-tuolene sulfuric acid the corresponding l t-ethylenedioxyderivative, 4b-methyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6, 7,8,10,10adodecahydrophenanthrene 1,4 diol is obtained.- Oxidizing this compoundby reaction with aluminum isopropoxide in the presence of cyclohexanoneformsa mixture containing4b-methyl-7-ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene- 1,4-dione and the corresponding 4-ol-1-onecompound which can be separated and recovered by fractionalcrystallization and/or chromatography. The-products so obtained canbeconverted to the corresponding 2,4b-di-. methyl compounds by firstreacting the compounds with methyl formate in the presence of sodiumhydride to obtain the 2-formyl derivatives, then reacting the formylderivatives with methyl iodide in the presence of anhydrous potassiumcarbonate to produce the 2-formyl-2- methyl derivatives, and finallysubjecting these latter derivatives to hydrolysis by chromatography overalkaline alumina to obtain respectively, 2,4b-dimethyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1,4-dione and thecorresponding 4-ol-1-one com pound. Reaction of the latter compoundswith a methallylhalide in the presence of an alkali metal or a metalalkoxide yields the corresponding Z-methallyl compounds used as startingmaterials in this application.

The following examples are presented for the purpose of illustratingmethods of carrying out my invention.

EXAMPLE 1 1 ethoxyethinyl 2,4b dimethyl 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro phenanthrene-1-0l-4-0ne Asolution of ethyl magnesium bromide (0.1526 m.) was prepared in theusual manner from 3.7 g. of magnesium and excess ethyl bromide in ml. ofdry ether. A solution of 11.74 g. of ethoxyacetylene (0.165 m.) dilutedwith dry ether to a total volume of 40 ml. was added gradually to theethyl Grignard and stirred until the evolution of ethane ceased. ml. ofdry benzene was added to dissolve the ethoxyacetylene magnesium bromide.

A solution of 27 g. of dry 2,4b-dimethyl-2-methallyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1,4-dione (M. P.108-109" C.) in ml. of dry benzene was added rapidly to the stirredGrlgnard solution. After standing at room temperature for two hours, thereaction mixture was decomposed by pouring into ice-Water. Enoughsaturated aqueous ammonium chloride was added to break the emulsionwhich formed. The benzene-ether layer was separated and washed once withwater. The aqueous layer was extracted again with 500 ml. of a 1:1benzene-ether solutron which, after one water wash, was combined withthe original extract. After drying over anhydrous sodium sulfate andremoval of the latter by filtration, the solvents were distilled invacuo. From a solution of the residual 011 In ether were obtainedcrystals of the desired product, M. P. 133-134 C.

By using a stereochemical modification of the above starting material,vM. P. 138-l39 C., and treating as above described, two stereochemicalmodifications of lethoxyethinyl-2,4b-dimethyl 2 methallyl, 'l ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l-o1-4-onewere obtained, M. P. 131-132 C. and M. P. 159-161 C.

To a solution of ethyl magnesium bromide in 25 cc;

of ether, prepared from 0.27 g. of magnesium (0.011 m.)

and excess ethyl bromide, was added 1.2 g. of ethoxyacetylene. Theresulting solid ethoxyacetylene magnesium bromide was dissolved by theadditionof 25 cc. of dry benzene. To this solution was added 1.00 g.(0.00277 m.) of crystalline 2,4b-dimethyl-2-methallyl-7-ethylene'dio'xy'1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol-l-one. Afterstanding twenty hours at room temperature, the homogeneous reactionmixture was .poured into ice-water and extracted with ether. Am-

EXAMPLE 3 -1 allyl 2,4b dimethyl 2 methallyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-l ,4-diol To 10 g. of2,4b-dimethyl-2-methallyl-7-ethylenedioxyl,2,'3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4- 'ol-l-one was added with rapid stirring, 150ml. of an approximately 0.5 m. ether solution of allyl magnesiumbromide. The resulting mixture was stirred for one hour at roomtemperature and then 5 ml. of water was added dropwise, with cooling.The ether solution was decanted, and the residue extracted with 150 ml.of ether. The combined ether solutions were concentrated in vacuo to ayellow gum. This gum was adsorbed on alumina from a benzene-petroleumether solution. Elution with petroleum ether-ether gave 1 allyl 2,4bdimethyl 2- methallyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-diol as a colorless amorphous solid.

Upon hydrolysis with acid, the ethylenedioxy substituent of 1allyl-Z,4b-dimethyl-2-methallyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenam EXAMPLE 4 1 ethinyl 2,4bdimethyl 2 methallyl 7 ethylene-- dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanzhren e-l-ol-4-one A flame-dried 100 cc. flask, fittedwith a potassium hydroxide drying tube, was cooled in a Dry Ice-acetonebath and charged with about -25 cc. of liquid ammonia. Metallic lithium(0.18 g., 0.0257 m.) was dissolved the ammonia and dry acetylene bubbledthrough the solution until the blue color disappeared. To the resultantsuspension of white lithium acetylide was added dropwise with stirring,over a five minute period, a solution of 0.97 g. (0.00271 m.) of2,4b-dimethyl-2-methallyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-l,4-dione dissolved in 25 cc. of 1:1benzene-ether solution. The flask was then removed from the Dry Ice bathand allowed to come to room temperature (stirring and slow acetyleneintroduction continued). This required about 45 minutes, most of theammonia boiling off during this time. The stirring and acetyleneaddition'were continued for an additional-45 minutes at roomtemperature. 20 cc. of water was then slowly added and the layersseparated. The aqueous portion was-extracted'twice with chloroform andthe combined chloroform-ether-benzene extract dried over magnesiumsulfate. Concentration gave a crystalline residue "of 1- ethinyl 2,4bdimethy 2 methallyl-7 ethylene'dioxy- 1,2;3,4j4a-,4b,5,6,7,8,10,10adodecahydrophen'an'threnel '10 01 4 one, M. P. 220-222 C.Recrystallization from ethyl acetate raised the melting point to223.5-224.5 C.

EXAMPLE 5 1 ethinyl 2,4b dimethyl 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenant hrene 1 ol 4 one Asolution of 1.8 g. (0.005 m.) of 2,4b dimethyl 2- methallyl 7ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1,4dione in 30 cc. of benzene was dried by the distillation of 20 cc. ofbenzene. After cooling to room temperature 20 cc. of 4% potassium .int-butanol (0.020 m.) was added. ,Dry acetylene gas was bubbled-throughthe resulting cherry .red solu tion for two hours. Then an additional40cc. of benzene was added to the reaction mixture and it was pouredinto 35 cc. of water. After separation of the layers the aqueous layerwas extracted twice more with benzene, the combined benzene extractsdried over magnesium sulfate, and concentrated. The residue consisted ofcrystals and a yellow 'oil. Recrystallization from ethyl acetate yieldedpurified 1 ethinyl 2,4b dimethyl 2 methallyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7 ,8,10,10a dodecahydrophenanthrene -"1 ol 4 one, M.P. 218-222 C.

EXAMPLE 6 1 ethinyl 2,4b dimethyl 2 methallyl 7 ethylenea'ioxy1,2,3,4,4a,4b,5,6,7,8,]0,]0a dodecahydrophenanthrene 1 ol '4 one A dryflask, cooled in-a Dry Ice-acetone bath, was charged with 50 cc. -.ofliquid ammonia and 0.9 g. (0.0231 m.) of metallic potassium. Dryacetylene was bubbled into the solution until "the deep blue color wasreplaced by a colorless suspension of potassium acetylide. Then 0.9 ,g.(0.0025 .m.) of 2,4b dimethyl 2 methallyl 7 .ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrop'henanthrene 1.,4 dione,dissolved in 50 cc. of 1:1 benzene-ether, was added rapidly from adropping funnel. Theipink suspension was removed from the cold bath andstirring and acetylene bubbling continued as the mixture warmedtto about20 C. with con comitant evaporation of the ammonia. During this time the.color changed from .pink "through .purple to brown. When thetemperature reached about 20 C. the mixture-was poured slowly into 20cc. of water, separated, and the aqueous layer extracted twice more withbenzene. The combined extracts were dried over magnesium sulfate and thebenzeneremoved in vacuo, leaving a residue consisting of crystals and ayellow oil. The oil was substantially removed by washing with coldmethanol, 'leaving crystalline 1 ethinyl 2,4b dimethyl 2 methallyl 7ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1 .ol4 one, M. P. 212- 220 C. Further purification was effected byrecrystallization from ethyl acetate to give material melting at 220-222C.

EXAMPLE 7 Oxidation of 1 allyl 2,4b dimethyl 2 methallyl- 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene J ,4diol To a solution of 5 g. of l allyl 2,4b dimethyl 2- methallyl 7ethylenedioxy .1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1,4diol in 50 ml. of dry pyridine was added a suspension of 5g. of chromiumtrioxide in 50 ml. of pyridine. The mixture was shaken well, and afterstanding for 1'6'hours .atroom temperature,was diluted with 400 ml. ofwater and extracted with four 250ml. portions of ether. The combinedether extracts were evaporated to an oil which, upon crystallizationfrom ether, gaveJl allyl -.2,4b dimethyl 2 methallyl 7 ethylenediox-y1,2,3,4,4a,'4b,5,6,7,8,10,10adodecahydrophenanthrene -'l- 01-4 one as-amixture of isomers, M. P. -127- 'l42="C. Adsorption 'o'f 2 g. of'thisEXAMPLE 8 1 carbomethoxymethyl 2,4b dimethyl 2 methallyl- 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecawith 2.5 g. of Zn(dried after activation with dilute hydrochloric acid) and 0.75 ml. ofmethyl bromoacetate. After a short induction period the reaction startedand a light yellow oily precipitate appeared which coated the zinc. Fouradditional portions of zinc (2.5 g.) and methyl bromoacetate (0.5 ml.)were added over a 24 hour period, the entire reaction being conducted atreflux temperature. The reaction mixture was then decomposed by thecantious addition of gladical aectic acid to the oily precipitate. Afteraddition of water the ether layer was separated and washed with cold 1 Nammonium hydroxide until the washings no longer were yellow. After afinal water wash the ethereal solution was dried over sodium sulfate,separated from the drying agent, and evaporated. Pure 1-carbomethoxylmethyl -2,4b dimethyl 2 methallyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,102. dodecahydrophenanthrene-l-ol-4-one, M. P.178179 C., was isolated from the benzene solution of the crude residue,on alumina, by chromatography and elution with petroleum ether-ether(6:4).

Upon hydrolyzing 1-carbomethoxymethyl-2,4b-dimethyl 2 methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,-

8,10,10a-dodecahydrophenanthrene-1-01-4-one with acid, the ethylenedioxysubstituent is cleaved to form l-carbomethoxymethyl 2,4b dimethyl 2methallyl 1,2,3,4,-

4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene-1-ol-4, 7-

dione.

EXAMPLE 9 Preparation of 2,4b dimethyl 1 ethoxyethinyl 2- methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,-10a-dodecahydrophenanthrene-I-0l-4-0ne Ethylmagnesium bromide wasprepared from 680 mg.

(0.0280 mole) of magnesium in ml. of ether in the usual fashion andtreated with an excess of ethoxyacetylene in ether. When the evolutionof ethane had ceased,

the oily Grignard reagent was dissolved by the addition of 20 ml. ofbenzene. To the resulting homogeneous brown solution was added in oneportion a solution of 5.00 g. (0.0140 mole) of2,4b-dimethyl-2-methallyl-7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-1,4-dione in ml. ofbenzene. After four hours at room temperature, the homogeneous reactionmixture was poured into ice-water. Ether was added and then saturatedammonium chloride solution in a quantity just sufficient to break theemulsion that had formed. The aqueous layer was separated and extractedtwice with ether. The combined organic extract was washed with water,dried and concentrated in vacuo. A benzene solution of the crudecrystalline product was adsorbed on alkaline alumina. With 1:1ether-petroleum ether there was eluted 4.57 g. (76%) of2,4b-dimethyl-l-ethoxyethinyl 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-l-ol-one, M. P.125 131 C. The analytical sample melted at 131132 C. afterrecrystallization from ether; A max. 2.76, 4.48, 5.90, 6.08 11..

. i 12 Analysis.Calcd. for C H O C, 72.86; H, 8.47. Found: C; 72.88; H,8.36. I Further elution with ether yielded 590 mg. (9.8%) of theisomeric 2,4b-dimethyl-l-ethoxy ethinyl-2-methallyl-7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one meltingat 150-161" C. Recrystallization from ether gave a sample with M. P.159-161 ,C.; x max. 2.85, 4.50, 5.90, 6.08

Analysis.-Found: C, 72.81; H, 8.24.

EXAMPLE 10 Preparation of 2,4b,dimethyl-1-carbethoxymethyl-Z-methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1011-r dodecahydrophemmthrene-J-0l4-0ne One-quarter milliliter of 10% sulfuric acid was added to asolution of mg. of 2,4b-dimethyl-l-ethoxyethinyl- 2 methallyl 7ethylenedioxy l,2,3,4,4a,4b,5,6,7,8','10,lOa-dodecahydrophenanthrene-1-ol-4-one melting at 161 C. in 4 ml. oftetrahydrofuran. After seven hours at room temperature, the reactionmixture was poured into excess sodium bicarbonate solution and thetetrahydrofuran was removed in vacuo. The product was extracted withether and chromatographed over 4.5 g. of alkaline alumina. With 3:7ether-petroleum ether there was eluted 109 mg. (75%) of2,4b-dimethyll-carbethoxymethyl-2- methallyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,l0, l0a-dodecahydrophenanthrene-l-ol-4-one meltingat 114- 118 C. The analytical sample had a melting point of 118-119" C.after recrystallization from petroleum ether; A max. 2.83, 5.83, 6.03[.L.

Analysis.--Calcd. for C H O C, 69.93; H, 8.58. Found: C, 70.26; H, 8.50.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of my invention.

I claim:

1. The process which comprises reacting 2,4b-dimethyl- 2 methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-1,4-dione with ethoxyacetylene magnesiumbromide and hydrolyzing the resulting reaction product to obtain1-ethoxyethinyl-2,4b-dimethyl= 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10;

10a-dodecahydrophenanthrene-l-ol-4-one.

2. The process which comprises reacting 2,4b-dimethyl- 2 methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,l0a-dodecahydrophenanthrene-4-ol-l-one with ethoxyacetylene magnesiumbromide and hydrolyzing the resulting reaction product to obtain1-ethoxyethinyl-2,4b-dimethyl- 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,

10a-dodecahydrophenanthrenel ,4-diol.

3. The process which comprises reacting 2,4b-dimethyl- 2 methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,lOa-dodecahydrophenanthrene-1,4-dione with allyl magnesium bromide andhydrolyzing the resulting reaction product to obtain1-allyl-2,4b-dimethyl-2-methal1yl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-ol-4-one.

4. The process which comprises reacting 2,4b-dimethyl- 2 methallyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol-l-one with allyl mag, nesium bromideand hydrolyzing the resulting reaction product to obtain1-allyl-2,4b-dimethyl-2-methallyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1,4-diol.

5. 1 ethoxyethinyl 2,4b dimethyl 2 methallyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodeca hydrophenanthrene-l-ol-4-one.

6. A stereochemical modification of l-ethoxyethinyl- 2,4b dimethyl 2methallyl 7 ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 1 ol-4-one, melting at about 133134 C.

7. A stereochemical modification of 1 ethoxyethinyl- 2,4b dimethyl 2methallyl 7 ethylenedioxy 1,2,3,

13 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1- ol-4-one, meltingat about l31-l32 C.

8. 1 ethovyethinyl 2,4b dimethyl 2 methallyl- 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1,4-diol.

9. 1 allyl 2,4b dimethyl 2 methallyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1,4-diol.

10. 1 allyl 2,4b dimethyl 2 methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one.

11. The process which comprises reacting a member from the groupconsisting of 7-loWer alkylene ketal and 7-lower alkyl-enol etherderivatives of a compound of the formula r C=CH2 wherein R is a memberfrom the group consisting of hydroxyl and keto, with a magnesium saltfrom the group consisting of allyl magnesium halides and ethoxyacetylenei4 magnesium halides to produce the corresponding'7-tierivatives of theformula wherein R is the same as defined above and R is a substituentfrom the group consisting of allyl and ethoxyethinyl.

12. A dodecahydrophenanthrene compound from the group consisting ofcompounds of the formula wherein R is a member from the group consistingof hydroxyl and keto and R is a member from the group consisting ofallyl and ethoxyethinyl, and the 7-lower alkyl-enol ethers and the7-1ower alkyl-ketal derivatives thereof.

No references cited.

12. A DODECAHYDROPHENANTHRENE COMPOUND FROM THE GROUP CONSISTING OFCOMPOUNDS OF THE FROMULA